CN111362934A - Isothiazole oxadiazole derivatives, and preparation method and application thereof - Google Patents
Isothiazole oxadiazole derivatives, and preparation method and application thereof Download PDFInfo
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- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention provides a class of isothiazole oxadiazole derivatives, a preparation method and application thereof, and particularly relates to a class of 3, 4-isothiazole-5-oxadiazole derivatives, which have a chemical structure general formula shown in formula IV:
Description
Technical Field
The technical scheme of the invention relates to isothiazole oxadiazole compounds, in particular to 3, 4-dichloroisothiazole-5-oxadiazole derivatives.
Background
The heterocyclic compound is an organic compound having a heterocyclic structure in a molecule, and the atoms constituting the ring contain at least one hetero atom in addition to carbon atoms. Heterocyclic compounds are very widespread in nature, are vital for life, and play a vital role in the metabolism of all living cells. Isothiazole and oxadiazole hybrids, which are explored in a wide variety of heterocycles for the development of pharmaceutically important molecules, play a crucial role in pharmaceutical chemistry.
Pest control is an indispensable link in agricultural production processes, at present, biological control, chemical control and physical control are common measures for controlling agricultural diseases, pests and weeds, wherein the chemical control is the most common and effective measure, but the chemical control is easy to destroy ecological environment and cause potential defects of drug resistance, and isotianil (isotianil) (strict intelligence, isotianil of Bayer corporation is approved in Japan [ J ] pesticide research and application, 2010 (5): 41-43) is an isothiazole fungicide which is developed and used for controlling rice blast by Bayer and Sumitomo chemistry together. It is characterized in that the rice blast resistance rice is achieved by exciting the natural defense mechanism of rice to the rice blast without generating direct antibacterial action to pathogenic bacteria. The commercial small-molecule plant activator also comprises probenazole (Nagata T, et al. JP2007186509[ P ].2007-07-26.) developed by Nippon Mingzhi fruit Co., Ltd. and Dichlorobentiazox (Nagaia T, et al. WO2007129454[ P ].2007-11-15) developed by Nippon combinatorial chemistry industry Co., Ltd.), has no obvious influence on the normal development of plants, has no direct killing effect on pathogenic bacteria, and has no resistance problem.
The oxadiazole structure is a unique conjugated system consisting of two nitrogen atoms and one oxygen atom, has stable structure, has hydrogen bond acceptor characteristics in a five-membered ring structure, and can improve the lipophilicity and the pharmacokinetic characteristics of the drug to a certain extent (Senthilkumar et al world Journal of Pharmaceutical Research, Vol 8, Issue 3, 2019, 1407.). A pesticide chemical researcher can derive a compound with a complex structure by changing a substituent group, expand the functions of the oxadiazole compound and discover a pesticide variety with high-efficiency, low-toxicity and broad-spectrum biological activity. Related documents and patents also report that compounds containing oxadiazole group have antibacterial, antifungal, insecticidal, herbicidal, anticancer, anti-inflammatory, etc. activities. Among the commercial pesticides containing oxazole structures are the insecticide famone (methoxazone), the herbicide oxadiazon (oxazizone), and the nematicide tioxafen, among others. The bactericides methylsulfonylconazole and fluorobenzyloxazole sulfone are being developed industrially.
When pathogens invade plants, the compound which can induce a plant generating system to obtain disease resistance and has bactericidal activity can not only solve the harm of pathogens, but also improve the self-defense capability of the plants and protect the plants from the invasion of subsequent pathogens. Therefore, the invention introduces the group containing 3, 4-dichloroisothiazole with induced disease-resistant activity into the same molecule to design and synthesize a class of isothiazole oxadiazole derivatives, and simultaneously carries out systematic screening and evaluation on the biological activity so as to discover more green pesticide candidate varieties with high activity, low resistance risk and high environmental compatibility.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: provides a synthetic method of substituted isothiazole oxadiazole derivatives, provides biological activity of the compounds for regulating and controlling agricultural, horticultural and sanitary and forestry plant pathogens and a determination method thereof, and simultaneously provides application of the compounds in the agricultural field, the horticultural field, the forestry field and the sanitary field.
The technical scheme adopted by the invention for solving the technical problem is as follows: the general chemical structure formula of a class of isothiazole oxadiazole derivatives with bactericidal activity in the agricultural field, the horticultural field and the forestry field is shown as IV:
r is selected from: hydrogen, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C2-C6Alkenyl radical, C2-C6Haloalkenyl, C2-C6Alkynyl, C2-C6Halogenated alkynyl, hydroxy, C3-C6Cycloalkyl, substituted piperidin-1-yl, substituted morpholin-1-yl, substituted tetrahydropyrroln-1-yl, phenyl, or halogen substituted phenyl, or C1-C6Alkyl-substituted phenyl or C1-C6Haloalkyl-substituted phenyl or C3-C6Cycloalkyl-substituted phenyl, or nitro-substituted phenyl, or C2-C6Phenyl substituted by alkenyl, or C2-C6Phenyl substituted by haloalkenyl, or C3-C6Phenyl substituted by cycloalkenyl, or C2-C6Alkynyl-substituted phenyl or C2-C6Phenyl or C substituted by haloalkynyl3-C6Cycloalkynyl-substituted phenyl, pyridyl, or halogen-substituted pyridyl, or C1-C6Alkyl-substituted pyridyl, or C1-C6Haloalkyl-substituted pyridyl, or C3-C6Cycloalkyl-substituted pyridyl or nitro-substituted pyridyl, or C2-C6Alkenyl-substituted pyridyl, or C2-C6Haloalkenyl-substituted pyridyl, or C3-C6A cycloalkenyl-substituted pyridyl group,Or C2-C6Alkynyl-substituted pyridyl or C2-C6Halogenoalkynyl-substituted pyridyl or C3-C6Cycloalkynyl-substituted pyridyl, pyrimidinyl, or halo-substituted pyrimidinyl, or C1-C6Alkyl-substituted pyrimidinyl, or C1-C6Pyrimidinyl substituted by haloalkyl, or C3-C6Cycloalkyl-substituted pyrimidinyl, or nitro-substituted pyrimidinyl, or C2-C6Alkenyl-substituted pyrimidinyl, or C2-C6Pyrimidinyl substituted by haloalkenyl, or C3-C6Pyrimidinyl substituted by cycloalkenyl, or C2-C6Alkynyl-substituted pyrimidinyl or C2-C6Halogenoalkynyl-substituted pyrimidinyl or C3-C6A cycloalkynyl-substituted pyrimidinyl group, a substituted five-or six-membered heteroaryl group containing 1 or 2N atoms, a substituted five-or six-membered heteroaryl group containing 1 or 2S atoms, a substituted five-or six-membered heteroaryl group containing 1 or 2O atoms, a substituted five-or six-membered heteroaryl group containing 1N atom and 1S atom, a substituted five-or six-membered heteroaryl group containing 1N atom and 1O atom, a substituted five-or six-membered heteroaryl group containing 2N atoms and 1S atom, a substituted five-or six-membered heteroaryl group containing 2N atoms and 1O atom; the five-or six-membered heteroaryl group is selected from: substituted furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, benzothienyl, benzofuranyl, benzimidazolyl, indazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, isomerized quinolinyl, isomerized isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl or naphthyridinyl, alkyl-or alkenyl-substituted silicon groups.
Halogen in the above definitions is fluorine, chlorine, bromine or iodine;
the alkyl, alkenyl or alkynyl is a linear or branched alkyl; alkyl is selected by itself or as part of another substituent from methyl, ethyl, propyl, butyl, pentyl, hexyl and isomers thereof selected from isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl or tert-pentyl;
the haloalkyl group is selected from the group consisting of one or more of the same or different halogen atoms, and the haloalkyl group is selected from CH2Cl、CHCl2、CCl3、CH2F、CHF2、CF3、CF3CH2、CH3CF2、CF3CF2Or CCl3CCl2；
The cycloalkyl group is selected by itself or as part of another substituent from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
the alkenyl group is selected as such or as part of another substituent from vinyl, allyl, 1-propenyl, buten-2-yl, buten-3-yl, penten-1-yl, penten-3-yl, hexen-1-yl or 4-methyl-3-pentenyl;
the alkynyl group is selected by itself or as part of another substituent from ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, 1-methyl-2-butynyl, hexyn-1-yl or 1-ethyl-2-butynyl.
The synthesis method of the isothiazole oxadiazole derivative comprises the following steps:
wherein the substituent R is as defined above; r is preferably selected from: 4-tert-butylphenyl, 4-trifluoromethoxyphenyl, phenyl, 3-difluoromethyl-1-methylpyrazol-4-yl, m-fluorophenyl, 2-chloropyridin-3-yl, thiophen-2-yl, 4-fluoronaphthyl, 2, 4-dichlorophenyl, 3-chloro-4-fluorophenyl, hydrogen, 5-difluoromethyl-1- (4-chlorophenyl) -pyrazol-4-yl, 5-trifluoromethyl-1- (3-fluorophenyl) -pyrazol-4-yl, 5-trifluoromethyl-1- (4-bromophenyl) -pyrazol-4-yl, 5-trifluoromethyl-1- (4-fluorophenyl) -pyrazol-4-yl, methyl-l-methyl, ethyl-l-4-yl, ethyl-methyl-, 5-trifluoromethyl-1- (4-chlorophenyl) -pyrazol-4-yl, 5-difluoromethyl-1- (2, 4-dichlorophenyl) -pyrazol-4-yl, pyridin-3-yl, o-chlorophenyl, 2-methylthiazol-4-yl, furan-2-yl, 2, 4-xylyl, o-fluorophenyl, trifluoromethyl.
The specific method for synthesizing the isothiazole oxadiazole derivative and measuring the biological activity comprises the following steps of:
A. preparation of compound II:
adding 3 mmol of compound I into a 100 ml reaction round-bottom flask, adding a solvent ethanol solution, adding 6 mmol of hydroxylamine hydrochloride after dissolution, finally dropwise adding 6 mmol of triethylamine, and stirring at room temperature for 1 hour; after the reaction is completely monitored by a point plate, decompression concentration is carried out, the solvent is removed, ethyl acetate is used for dilution, water washing is carried out, ethyl acetate is used for extraction for 3 times, organic layers are combined, saturated sodium chloride is used for washing the organic layers, anhydrous sodium sulfate is used for drying, suction filtration is carried out, the solvent is removed under reduced pressure, the residue is purified through 100-200-mesh silica gel column chromatography, the eluent is petroleum ether and ethyl acetate with the temperature of 60-90 ℃, the volume ratio is 3: 1, and a yellow solid compound II is obtained, and the yield is 98%. The amount of compound II prepared and the volume of the reaction vessel are scaled up or down accordingly.
B. Preparation of compound IV:
adding 3 mmol of a compound II into a 100 ml round-bottom flask, adding a solvent dichloromethane solution and an acid-binding agent triethylamine, cooling to zero degree in an ice bath, dissolving III in dichloromethane, slowly dropwise adding into the reaction solution, stirring for half an hour, adding 12 mmol of tetrabutylammonium fluoride, and stirring for 3 hours at room temperature; after the reaction is completely monitored by a point plate, decompression concentration is carried out, the solvent is removed, ethyl acetate is used for dilution, water washing is carried out, ethyl acetate is used for extraction for 3 times, organic layers are combined, saturated sodium chloride is used for washing the organic layers, anhydrous sodium sulfate is used for drying, suction filtration is carried out, the solvent is removed under reduced pressure, the residue is purified through 100-200-mesh silica gel column chromatography, the eluent is petroleum ether and ethyl acetate at the temperature of 60-90 ℃, the volume ratio is 30: 1-15: 1 according to the characteristics of products, and the solid compound IV is obtained, and the yield is 30-70%. The amount of compound IV prepared and the volume of the reaction vessel are scaled up or down accordingly.
C. The invention relates to a determination method of the bactericidal activity of a class of isothiazole oxadiazole derivatives IV, which comprises the following steps:
the bactericidal or bacteriostatic activity of the isothiazole oxadiazole derivative IV is determined by a thallus growth rate method, and the method comprises the following specific steps: dissolving 1.8 mg of sample in 2 drops of N, N-dimethylformamide, diluting with a water solution containing a certain amount of Tween 20 emulsifier to 500 micrograms/ml of medicament, sucking 1 ml of the medicament to be tested in a culture dish under an aseptic condition, adding 9 ml of PDA culture medium, shaking uniformly to prepare a medicament-containing flat plate with the concentration of 50 micrograms/ml, taking the flat plate added with 1 ml of sterile water as a blank control, cutting a bacterial disc by a puncher with the diameter of 4 mm along the outer edge of hypha, moving the bacterial disc to the medicament-containing flat plate, placing the bacterial disc in an equilateral triangle, repeating the treatment for 3 times, placing the culture dish in a constant temperature incubator with the temperature of 24 +/-1 ℃ for culture, investigating the expansion diameter of each treated bacterial disc after the diameter of the control bacterial colony is expanded to be more than 2 cm, calculating the relative bacteriostasis rate by comparing with the blank control, wherein the strain is the species of most typical plant pathogenic bacteria actually generated in the field in agricultural production of China, the code numbers and names are as follows: AS: tomato early blight, its latin name is: alternaria solani, BC: the cucumber botrytis cinerea with the latin name as follows: botrytis cinerea, GZ: wheat scab, its latin name is: gibberella zeae, PI: the late blight of potato, its latin name is: phytophthora infestans (Mont.) de Bary, PP: apple ring rot, its latin name is: physiosporia piricola, PS: rhizoctonia solani, the Latin name of which is: pellicularia sasakii, RC: rhizoctonia cerealis, with the latin name: rhizoctonia cerealis, SS: sclerotinia sclerotiorum, its latin name is: sclerotina sclerotiorum.
The invention has the beneficial effects that: the method is characterized in that a class of isothiazole oxadiazole derivatives IV is subjected to lead optimization, and a class of isothiazole oxadiazole derivatives IV is screened for antibacterial activity.
The synthesis, biological activity and application of a substituted isothiazoloxadiazole derivative IV are more specifically illustrated by specific preparation and biological activity determination examples, which are only used for specifically illustrating the invention and not limiting the invention, and particularly, the biological activity is only illustrated and not limiting the patent, and the specific embodiments are as follows:
example 1: preparation of Compound IV-1:
adding 3 mmol of a compound II into a 100 ml round-bottom flask, adding 30 ml of dichloromethane solution and 4 mmol of a compound acid-binding agent triethylamine, cooling to zero degree in ice bath, dissolving III-1 with dichloro, slowly dropwise adding into the reaction solution, stirring for half an hour, adding 12 mmol of tetrabutylammonium fluoride, and stirring for 3 hours at room temperature; after the reaction is completely monitored by a point plate, decompression concentration is carried out, the solvent is removed, ethyl acetate is used for dilution, 20 ml of water washing is carried out, ethyl acetate is used for extraction for 3 times, organic layers are combined, the organic layers are washed by saturated sodium chloride, anhydrous sodium sulfate is used for drying, suction filtration is carried out, the solvent is removed under reduced pressure, the residue is purified by 100-200-mesh silica gel column chromatography, the eluent is petroleum ether and ethyl acetate with the temperature of 60-90 ℃, the volume ratio of the petroleum ether to the ethyl acetate is 15: 1, a white solid compound IV is obtained, and the yield is. Of the compound1H NMR (400MHz, CDCl3) δ 8.40(s, 1H), 7.56(dd, J ═ 14.3, 6.7Hz, 1H), 7.32(dd, J ═ 18.3, 8.1Hz, 3H). The physicochemical and structural parameters of compound IV are shown in Table 1.
Example 2: preparation of Compound IV-2:
adding 3 mmol of a compound II into a 100 ml round-bottom flask, adding 30 ml of dichloromethane solution and 4 mmol of a compound acid-binding agent triethylamine, cooling to zero degree in ice bath, dissolving III-2 with dichloromethane, slowly dropwise adding into the reaction solution, stirring for half an hour, adding 12 mmol of tetrabutylammonium fluoride, and stirring for 3 hours at room temperature; after the reaction is completely monitored by a point plate, the reaction is concentrated under reduced pressure, the solvent is removed, the reaction product is diluted by ethyl acetate, 20 ml of water is washed, ethyl acetate is extracted for 3 times, organic layers are combined, the organic layers are washed by saturated sodium chloride, dried by anhydrous sodium sulfate, filtered, the solvent is removed under reduced pressure, the residue is purified by 100-200 meshes silica gel column chromatography, the eluent is petroleum ether and ethyl acetate at the temperature of 60-90 ℃,the volume ratio is 15: 1, and white solid compound IV is obtained with the yield of 60%. Of the compound1H NMR (400MHz, DMSO) δ 8.39(d, J ═ 7.6Hz, 2H), 8.05(d, J ═ 7.7Hz, 2H) compound IV physicochemical and structural parameters are shown in table 1.
Example 3: the bactericidal activity determination result of a class of isothiazole oxadiazole derivatives IV of the invention is as follows:
the codes and names of the common plant pathogenic fungi tested by the invention are as follows: PI: the late blight of potato, its latin name is: phytophthora infestans (Mont.) de Bary, SS: sclerotinia sclerotiorum, its latin name is: sclerotina sclerotiorum, BC: the cucumber botrytis cinerea with the latin name as follows: botrytis cinerea, GZ: wheat scab, its latin name is: gibberella zeae, AS: tomato early blight, its latin name is: alternariolani, RC: rhizoctonia cerealis, with the latin name: rhizoctonia cerealis, PP: apple ring rot, its latin name is: physiosporia piricola, PS: rhizoctonia solani, the Latin name of which is: pellicularia sasakii, CA: peanut brown spot pathogen, its latin name is: cercospora arachidicola. These species represent the species of most pathogenic bacteria occurring in the field in agricultural production.
The results of the bacteria growth rate method are shown in table 2, and table 2 shows that most of the compounds of the invention have certain bacteriostatic activity on the tested bacteria under the in vitro condition at 50 micrograms/ml. The activity test result on potato late blight bacteria shows that the bacteriostatic activity of all the compounds is not high, but is higher than or equal to that of isotianil (the inhibition rate on potato late blight bacteria is 3%), wherein the ZS-10 activity is equal to that of thifluzamide (the inhibition rate on potato late blight bacteria is 20%), and the ZS-11 activity is higher than that of thifluzamide (the inhibition rate on potato late blight bacteria is 20%) and is more than 10%. The activity test of sclerotinia sclerotiorum shows that most of the compounds are higher than isotianil (the inhibition rate of sclerotinia sclerotiorum is 52%). Wherein the bacteriostatic activity of ZS-07 and ZS-11 is more than 90%, and the activity is equivalent to thifluzamide (the inhibition rate to Sclerotinia sclerotiorum is 91%). The activity test on the botrytis cinerea shows that the activity of the compound is lower, wherein the bacteriostatic activity of ZS-21 and ZS-11 is higher than that of isotianil (the inhibition rate on the botrytis cinerea is 43 percent), wherein the activity of ZS-11 is higher than 90 percent, and the activity of the compound is higher than that of a commercial fungicide thifluzamide (the inhibition rate on the botrytis cinerea is 87 percent). The activity test on wheat scab bacteria shows that the bacteriostatic activity of the compounds ZS-03, ZS-04, ZS-06, ZS-10, ZS-11, ZS-12, ZS-14, ZS-18, ZS-20, ZS-21, ZS-23 and ZS-24 is higher than that of isotianil (the inhibition rate on cucumber botrytis cinerea is 10%) by more than 18% and thifluzamide (the inhibition rate on cucumber gray mold bacteria is 20%) by more than 8%. The activity result on the early blight bacteria of tomato shows that the bacteriostatic activity of all the compounds is higher than or equal to that of isotianil (the inhibition rate on the early blight bacteria of tomato is 11%), wherein the ZS-08 bacteriostatic activity is equal to that of thifluzamide (the inhibition rate on the early blight bacteria of tomato is 69%). The activity test on rhizoctonia cerealis shows that the compounds all show certain bacteriostatic activity, wherein ZS-11 shows more excellent bacteriostatic activity of 71 percent, which is higher than that of isotianil (the inhibition rate on rhizoctonia cerealis is 62 percent) and thifluzamide (the inhibition rate on rhizoctonia cerealis is 67 percent). The activity test on the ring rot of apple indicates that the activity of most compounds is higher than that of isotianil (the inhibition rate on the ring rot of apple is 20%), wherein the ZS-11 and ZS-12 bacteriostatic activity is basically equivalent to that of thifluzamide (the inhibition rate on the ring rot of apple is 69%). The activity test on rice sheath blight bacteria shows that all the compounds show certain bacteriostatic activity, wherein the activities of ZS-06, ZS-10, ZS-11, ZS-12, ZS-15, ZS-18, ZS-21 and ZS-22 are higher than those of isotianil (the inhibition rate on rice sheath blight bacteria is 11%) and thifluzamide (the inhibition rate on rice sheath blight bacteria is 17%). The activity test of peanut brown spot pathogen shows that part of the compounds have good bacteriostatic activity, wherein the bacteriostatic activity of ZS-10 and ZS-11 reaches more than 70 percent and is far higher than that of isotianil (the inhibition rate of peanut brown spot pathogen is 21 percent)
Example 4: the invention relates to an application of a 3, 4-dichloroisothiazole-5-oxadiazole derivative IV in preparing a pesticide composition, which comprises the following steps:
the isothiazole oxadiazole derivative IV can be compounded with other commercial insecticides, acaricides, bactericides, antiviral agents or plant activators to prepare a pesticide composition, the composition comprises the isothiazole oxadiazole derivative IV and an intermediate thereof as active ingredients, the mass percentage of the active ingredients and other commercial insecticides, acaricides, bactericides, antiviral agents or plant activators is 1% to 99% to 1%, the content of the active ingredients is 0.1 to 99.9% by weight, 99.9 to 0.1% by weight of a solid or liquid auxiliary agent, and optionally 0 to 25% by weight of a surfactant.
Example 5: the invention relates to application of a isothiazole oxadiazole derivative IV and an insecticide composition in preventing and treating agricultural, forestry and horticultural plant insect pests:
all isothiazole oxadiazole derivatives IV of the invention are combined with any one or two of commercial insecticides to form an insecticidal composition for preventing and treating agricultural and forestry and horticultural plant insect pests; the commodity pesticide is a pesticide which is allowed to be registered and used by the agricultural administration part of China; the isothiazole oxadiazole derivatives IV and the intermediates thereof are 1-90 wt%, 99-10 wt% of solid or liquid auxiliary agents and optionally 0-25 wt% of surfactants in the insecticidal composition, wherein the mass percentage of the isothiazole oxadiazole derivatives IV and the commercial insecticide is 1: 99: 1; the insecticide composition is processed into a dosage form selected from the group consisting of: any one of a seed treatment emulsion, an aqueous emulsion, a macrogranule, a microemulsion, a water-soluble granule, a soluble concentrate, a water-dispersible granule, a poison valley, an aerosol, a block poison bait, a sustained-release block, a concentrated poison bait, a capsule granule, a microcapsule suspension, a dry-mixed seed powder, a missible oil, an electrostatic spray, an aqueous-in-oil emulsion, an oil-in-water emulsion, a smoke canister, a fine granule, a smoke candle, a smoke canister, a smoke stick, a seed treatment suspension, a smoke tablet, a smoke pellet, a granular poison bait, a hot fogging concentrate, a medicinal paint, a fine granule, an oil suspension, an oil-dispersible powder, a flaky poison bait, a concentrated colloid, a pouring agent, a seed coating agent, a smearing agent, a suspending emulsion, a film-forming oil agent, a soluble powder, a seed treatment water-soluble powder, an ultra-low-volume suspension, a chasing powder; the plant insect pests controlled by the insecticidal composition are common insect pests in farmlands; the plants controlled by the insecticidal composition are common grain crops and economic crops in agricultural production and horticultural crops.
Example 6: the invention relates to an application of a isothiazole oxadiazole derivative IV and a bactericide in preventing and treating agricultural, forestry and horticultural plant diseases, which comprises the following steps:
all isothiazole oxadiazole derivatives IV of the invention and any one or two of commercial bactericides form a bactericidal composition for preventing and treating plant diseases in agriculture, forestry and horticulture, and the commercial bactericides are bactericides which are allowed to be registered and used by the agricultural director of China; the total mass percentage of the isothiazole oxadiazole derivative IV in the bactericidal composition is 1% -90%, 99% -10% of solid or liquid auxiliary agent and optionally 0% -25% of surfactant, and the mass percentage of the isothiazole oxadiazole derivative IV in the bactericidal composition is 1% to 99% to 1%; the bactericidal composition is processed into a dosage form selected from the group consisting of: any one of a seed treatment emulsion, an aqueous emulsion, a macrogranule, a microemulsion, a water-soluble granule, a soluble concentrate, a water-dispersible granule, a poison valley, an aerosol, a block poison bait, a sustained-release block, a concentrated poison bait, a capsule granule, a microcapsule suspension, a dry-mixed seed powder, a missible oil, an electrostatic spray, an aqueous-in-oil emulsion, an oil-in-water emulsion, a smoke canister, a fine granule, a smoke candle, a smoke canister, a smoke stick, a seed treatment suspension, a smoke tablet, a smoke pellet, a granular poison bait, a hot fogging concentrate, a medicinal paint, a fine granule, an oil suspension, an oil-dispersible powder, a flaky poison bait, a concentrated colloid, a pouring agent, a seed coating agent, a smearing agent, a suspending emulsion, a film-forming oil agent, a soluble powder, a seed treatment water-soluble powder, an ultra-low-volume suspension, a chasing powder; the plant diseases controlled by the bactericidal composition are common plant diseases of farmlands; the plants suitable for the sterilizing composition are common grain crops, economic crops and horticultural crops in agricultural production.
Example 7: the invention discloses application of a isothiazole oxadiazole derivative IV and a plant virus resisting agent in preventing and treating virus diseases of agricultural, forestry and horticultural plants, which comprises the following steps:
all isothiazole oxadiazole derivatives IV of the invention are combined with any one or two of commercial antiviral medicaments to form an antiviral composition for preventing and treating virus diseases of agricultural, forestry and horticultural plants, wherein the commercial antiviral medicament is an antiviral medicament allowed to be registered and used by the agricultural director of China; the total mass percentage of the isothiazole oxadiazole derivative IV in the antiviral composition is 1% -90%, 99% -10% of solid or liquid auxiliary agent by weight and optionally 0% -25% of surfactant by weight, and the ratio of the isothiazole oxadiazole derivative IV in the antiviral composition to the commercial anti-plant virus agent is 1% to 99% to 1% by weight; the antiviral composition is processed into a dosage form selected from: any one of a seed treatment emulsion, an aqueous emulsion, a macrogranule, a microemulsion, a water-soluble granule, a soluble concentrate, a water-dispersible granule, a poison valley, an aerosol, a block poison bait, a sustained-release block, a concentrated poison bait, a capsule granule, a microcapsule suspension, a dry-mixed seed powder, a missible oil, an electrostatic spray, an aqueous-in-oil emulsion, an oil-in-water emulsion, a smoke canister, a fine granule, a smoke candle, a smoke canister, a smoke stick, a seed treatment suspension, a smoke tablet, a smoke pellet, a granular poison bait, a hot fogging concentrate, a medicinal paint, a fine granule, an oil suspension, an oil-dispersible powder, a flaky poison bait, a concentrated colloid, a pouring agent, a seed coating agent, a smearing agent, a suspending emulsion, a film-forming oil agent, a soluble powder, a seed treatment water-soluble powder, an ultra-low-volume suspension, a chasing powder; the virus diseases controlled by the antiviral composition are plant virus diseases common to farmlands; the plants suitable for the antiviral composition are common grain crops and economic crops in agricultural production and horticultural crops.
Example 8: the invention discloses application of a isothiazole oxadiazole derivative IV and an acaricide in preventing and treating mite damage of agricultural, forestry and horticultural plants, which comprises the following steps:
all isothiazole oxadiazole derivatives IV of the invention are combined with any one or two of commercial acaricides to form an acaricidal composition for preventing and controlling acarid damages of agricultural, forestry and horticultural plants, wherein the commercial acaricides are acaricides which are allowed to be registered in the agricultural director of China; the total mass percentage of the isothiazole oxadiazole derivative IV of the invention in the acaricidal composition is 1% -90%, 99% -10% of solid or liquid auxiliary agent by weight and optionally 0% -25% of surfactant by weight, and the mass percentage of the isothiazole oxadiazole derivative IV of the invention to the commercial acaricide is 1% -99% -1%; the acaricidal composition is processed into a dosage form selected from the following: any one of a seed treatment emulsion, an aqueous emulsion, a macrogranule, a microemulsion, a water-soluble granule, a soluble concentrate, a water-dispersible granule, a poison valley, an aerosol, a block poison bait, a sustained-release block, a concentrated poison bait, a capsule granule, a microcapsule suspension, a dry-mixed seed powder, a missible oil, an electrostatic spray, an aqueous-in-oil emulsion, an oil-in-water emulsion, a smoke canister, a fine granule, a smoke candle, a smoke canister, a smoke stick, a seed treatment suspension, a smoke tablet, a smoke pellet, a granular poison bait, a hot fogging concentrate, a medicinal paint, a fine granule, an oil suspension, an oil-dispersible powder, a flaky poison bait, a concentrated colloid, a pouring agent, a seed coating agent, a smearing agent, a suspending emulsion, a film-forming oil agent, a soluble powder, a seed treatment water-soluble powder, an ultra-low-volume suspension, a chasing powder; the mite damage prevented and controlled by the mite-killing composition is common plant virus mite damage in farmlands; the acaricidal composition is suitable for plants which are common grain crops and economic crops in agricultural production and horticultural crops.
TABLE 1 chemical structure and physicochemical parameters of a class of isothiazoloxadiazole derivatives IV of the present invention
TABLE 1 chemical structure and physicochemical parameters (continuance) of a class of isothiazoloxadiazole derivatives IV of the invention
TABLE 2 bacteriostatic activity of a class of isothiazoloxadiazole derivatives IV of the invention (inhibition rate of 50. mu.g/ml/%)
| Serial number | Numbering | PI | SS | BC | GZ | CA | AS | RC | PP | PS |
| 1 | ZS-01 | 3 | 48 | 24 | 10 | 8 | 25 | 19 | 29 | 11 |
| 2 | ZS-02 | 13 | 73 | 22 | 3 | 33 | 19 | 45 | 22 | 6 |
| 3 | ZS-03 | 3 | 57 | 28 | 34 | 33 | 19 | 48 | 12 | 8 |
| 4 | ZS-04 | 0 | 45 | 22 | 34 | 33 | 22 | 21 | 27 | 6 |
| 5 | ZS-05 | 13 | 57 | 22 | 3 | 13 | 28 | 26 | 29 | 6 |
| 6 | ZS-06 | 3 | 48 | 11 | 28 | 4 | 19 | 19 | 24 | 33 |
| 7 | ZS-07 | 3 | 91 | 11 | 10 | 17 | 25 | 14 | 25 | 6 |
| 8 | ZS-08 | 3 | 52 | 20 | 7 | 25 | 67 | 24 | 27 | 14 |
| 9 | ZS-09 | 3 | 52 | 22 | 0 | 13 | 19 | 19 | 20 | 14 |
| 10 | ZS-10 | 20 | 59 | 25 | 34 | 71 | 53 | 48 | 33 | 22 |
| 11 | ZS-11 | 33 | 100 | 91 | 66 | 83 | 56 | 71 | 76 | 44 |
| 12 | ZS-12 | 10 | 30 | 11 | 21 | 33 | 19 | 26 | 65 | 19 |
| 13 | ZS-13 | 3 | 57 | 22 | 0 | 8 | 11 | 14 | 18 | 17 |
| 14 | ZS-14 | 13 | 14 | 22 | 45 | 33 | 19 | 31 | 49 | 17 |
| 15 | ZS-15 | 12 | 78 | 33 | 16 | 0 | 25 | 30 | 36 | 27 |
| 16 | ZS-16 | 3 | 57 | 0 | 0 | 13 | 19 | 26 | 10 | 6 |
| 17 | ZS-17 | 7 | 57 | 0 | 0 | 8 | 11 | 14 | 20 | 11 |
| 18 | ZS-18 | 3 | 66 | 22 | 28 | 33 | 28 | 14 | 35 | 22 |
| 19 | ZS-19 | 3 | 55 | 11 | 10 | 25 | 14 | 14 | 25 | 11 |
| 20 | ZS-20 | 3 | 55 | 11 | 28 | 21 | 19 | 14 | 16 | 14 |
| 21 | ZS-21 | 9 | 72 | 54 | 41 | 16 | 28 | 55 | 39 | 38 |
| 22 | ZS-22 | 13 | 57 | 17 | 10 | 17 | 14 | 24 | 29 | 19 |
| 23 | ZS-23 | 3 | 77 | 11 | 31 | 33 | 14 | 14 | 20 | 14 |
| 24 | ZS-24 | 3 | 52 | 22 | 34 | 21 | 14 | 26 | 41 | 11 |
| 25 | Isotianil | 3 | 52 | 43 | 10 | 21 | 11 | 62 | 20 | 11 |
| 26 | Thifluzamide | 20 | 91 | 87 | 20 | 90 | 69 | 67 | 69 | 17 |
AS: tomato early blight, its latin name is: alternaria solani, PI: the late blight of potato, its latin name is: phytophthora infestans (Mont.) de Bary, SS: sclerotinia sclerotiorum, its latin name is: sclerotina sclerotiorum, BC: the cucumber botrytis cinerea with the latin name as follows: botrytis cinerea, GZ: wheat scab, its latin name is: gibberella zeae, RC: rhizoctonia cerealis, with the latin name: rhizoctoniacealis, PP: apple ring rot, its latin name is: physiosporia piricola, PS: rhizoctonia solani, the Latin name of which is: pellicularia sasakii, CA: peanut brown spot pathogen, its latin name is: cercosporarachidiacola.
Claims (7)
1. The isothiazole oxadiazole derivative is characterized by simultaneously containing isothiazole and oxadiazole structures and having a structural general formula shown in a formula IV:
wherein R is selected from: 4-tert-butylphenyl, 4-trifluoromethoxyphenyl, phenyl, 3-difluoromethyl-1-methylpyrazol-4-yl, m-fluorophenyl, 2-chloropyridin-3-yl, thiophen-2-yl, 4-fluoronaphthyl, 2, 4-dichlorophenyl, 3-chloro-4-fluorophenyl, hydrogen, 5-difluoromethyl-1- (4-chlorophenyl) -pyrazol-4-yl, 5-trifluoromethyl-1- (3-fluorophenyl) -pyrazol-4-yl, 5-trifluoromethyl-1- (4-bromophenyl) -pyrazol-4-yl, 5-trifluoromethyl-1- (4-fluorophenyl) -pyrazol-4-yl, methyl-l-methyl, ethyl-l-4-yl, ethyl-methyl-, 5-trifluoromethyl-1- (4-chlorophenyl) -pyrazol-4-yl, 5-difluoromethyl-1- (2, 4-dichlorophenyl) -pyrazol-4-yl, pyridin-3-yl, o-chlorophenyl, 2-methylthiazol-4-yl, furan-2-yl, 2, 4-xylyl, o-fluorophenyl, trifluoromethyl.
2. The specific synthetic route and method of the isothiazoloxadiazole derivative IV according to claim 1 are as follows:
the definition of the substituent is as defined in claim 1, and the specific synthetic method comprises the following steps:
A. preparation of intermediate II:
the intermediate II is prepared by stirring and reacting starting material I, hydroxylamine hydrochloride and triethylamine in solvent dichloromethane at room temperature, wherein the definitions of the starting material I and the intermediate II are defined in claim 1;
B. preparation of a class of isothiazoloxadiazole derivatives IV:
IV is prepared by stirring and reacting the intermediate II, the intermediate III, a solvent dichloromethane, an acid-binding agent triethylamine and tetrabutylammonium fluoride at room temperature; wherein, the definition of the substituent groups in the intermediate III and the target product isothiazoloxadiazole derivative IV is as defined in claim 1.
3. Use of a class of isothiazoloxadiazole derivatives IV and intermediates of claim 1 for the preparation of agricultural fungicides.
4. An agricultural fungicidal composition comprising the isothiazoloxadiazole derivative IV of claim 1 and an intermediate thereof, which can be prepared to contain the isothiazoloxadiazole derivative IV of claim 1 and an intermediate thereof as active ingredients in an amount of 0.1 to 99.9% by weight, 99.9 to 0.1% by weight of a solid or liquid adjuvant, and optionally 0 to 25% by weight of a surfactant.
5. An agricultural sterilization compound composition, which comprises the isothiazole oxadiazole derivative IV and the intermediate thereof in claim 1 and other commercial bactericides in a compound way to serve as active ingredients, wherein the mass percentage of the isothiazole oxadiazole derivative IV and the intermediate thereof to the other commercial bactericides is 1% to 99% to 1%, the content of the active ingredients is 1 to 99% by weight, and the weight of the active ingredients is 99 to 1% by weight of solid or liquid auxiliaries.
6. An agricultural insecticidal and acaricidal compound composition comprises the isothiazole oxadiazole derivatives IV and intermediates thereof in claim 1 and other commercial insecticidal and acaricidal agents as active ingredients, wherein the mass percentage of the isothiazole oxadiazole derivatives IV and the intermediates thereof to other commercial bactericides is 1 to 99 to 1, the content of the active ingredients is 1 to 99 percent by weight, and the content of the solid or liquid auxiliary agents is 99 to 1 percent by weight.
7. A plant activator compound composition comprises the isothiazole oxadiazole derivative IV and an intermediate thereof as claimed in claim 1 and other commercial plant activators as active ingredients, wherein the mass percentage of the isothiazole oxadiazole derivative IV and the intermediate thereof to other commercial bactericides is 1% to 99% to 1%, the content of the active ingredients is 1 to 99% by weight, and the weight of the active ingredients is 99 to 1% by weight of solid or liquid auxiliaries.
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| CN1894241A (en) * | 2002-08-09 | 2007-01-10 | 阿斯利康(瑞典)有限公司 | '1,2,4' oxadiazoles as modulators of metabotropic glutamate receptor-5 |
| CN108864075A (en) * | 2018-07-26 | 2018-11-23 | 南开大学 | A kind of isothiazole connection thiazole and its preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1894241A (en) * | 2002-08-09 | 2007-01-10 | 阿斯利康(瑞典)有限公司 | '1,2,4' oxadiazoles as modulators of metabotropic glutamate receptor-5 |
| CN108864075A (en) * | 2018-07-26 | 2018-11-23 | 南开大学 | A kind of isothiazole connection thiazole and its preparation method and application |
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